Benzylidene pyrano[4,3-c]pyrazoles

ABSTRACT

Compounds having the formula wherein R 1  is hydrogen, hydroxy, alkyl, alkoxy, alkylthio, trifluoromethyl, halogen, nitro, cyano, dialkylamino or alkylsulfinyl; and R 2  is hydrogen, alkyl, aryl, arylalkyl, acyl or an aminoalkylene have useful antiinflammatory activity.

BRIEF DESCRIPTION OF THE INVENTION

Pyrano [4,3-c] pyrazoles having the formula ##STR1##and thepharmaceutically acceptable salts thereof, have useful antiinflammatoryactivity. In formula I, and throughout the specification, the symbolsare as defined below.

R₁ can be hydrogen, hydroxy, alkyl, alkoxy, alkylthio, trifluoromethyl,halogen, nitro, cyano, dialkylamino or alkylsulfinyl; and

R₂ can be hydrogen, alkyl, aryl, arylalkyl, ##STR2## wherein X is alkylor aryl, or A-NR₃ R₄ wherein A is a straight or branched chain alkylenegroup having 2 to 5 carbon atoms, R₃ can be hydrogen or alkyl, and R₄can be hydrogen, alkyl, phenyl or phenylalkyl, or R₃ and R₄ togetherwith the nitrogen atom to which they are attached can be ##STR3##wherein Z can be CH₂, oxygen or N-R₅ wherein R₅ can be hydrogen, alkyl,aryl or arylalkyl.

The terms "alkyl" and "alkoxy" as used throughout the specification(individually or as part of a larger group) refer to groups having 1 to8 carbon atoms; alkyl and alkoxy groups having 1 to 3 carbon atoms arepreferred.

The term "halogen" as used throughout the specification refers tofluorine, chlorine, bromine and iodine; fluorine and chlorine arepreferred.

The term "aryl" as used throughout the specification (individually or aspart of a larger group) refers to phenyl or phenyl monosubstituted withan alkyl, alkoxy, halogen or trifluoromethyl group; phenyl is preferred.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I are prepared using as starting materials asubstituted tetrahydro-4H-pyran-4-one having the formula ##STR4## and ahydrazine having the formula

    H.sub.2 NNH-R.sub.2                                        III.

the compounds of formulas II and III are readily obtainable; see, forexample, Journal of the American Chemical Society, 79:156 (1957) andJournal of Medicinal Chemistry, 7:493 (1964).

A substituted tetrahydro-4H-pyran-4-one of formula II can be prepared byreacting tetrahydro-4H-pyran-4-one with an appropriate benzaldehydehaving the formula ##STR5##

A hydrazine of formula III can be prepared by reacting an excess ofhydrazine (H₂ NNH₂) with a compound having the formula

    R.sub.2 -Y                                                 V.

wherein Y is chlorine or bromine.

Reaction of a substituted tetrahydro-4H-pyran-4-one of formula II with ahydrazine of formula III yields a product of formula I. The reaction canbe run in an organic solvent, preferably a lower alkanol such asmethanol. While reaction conditions are not critical, the reaction willpreferably be run at, or near, the reflux temperature of the solvent.

Alternatively, compounds of formula I wherein R₂ is hydrogen can be usedas intermediates for the preparation of other compounds of formula I, byreaction with alkylating and acylating agents using procedures wellknown in the art.

Still another method for preparing the compounds of formula I wherein R₂is A-NR₃ R₄ comprises first reacting a substitutedtetrahydro-4H-pyran-4-one of formula II with a hydroxyalkyl hydrazinehaving the formula

    H.sub.2 NNH-A-OH                                           VI.

to form an intermediate having the formula ##STR6##An alcohol of formulaVII can be reacted with an alkylsulfonyl or arylsulfonyl halide,preferably p-toluenesulfonyl halide, to yield a compound of the formula##STR7## wherein Y is alkyl or aryl. The intermediate of formula VIIIcan be treated with a compound having the formula

    HNR.sub.3 R.sub.4                                          IX.

to yield the products of formula I. This method is particularly usefulin preparing those compounds of formula I wherein R₂ is A-NR₃ R₄, and R₃and R₄ are both hydrogen.

The compounds of formula I wherein R₂ is aminoalkylene form acidaddition salts with inorganic and organic acids. These acid additionsalts frequently provide useful means for isolating the products fromreaction mixtures by forming the salt in a medium in which it isinsoluble. The free base may then be obtained by neutralization, e.g.,with a base such as sodium hydroxide. Any other salt may then be formedfrom the free base and the appropriate inorganic or organic acid.Illustrative are the hydrohalides, especially the hydrochloride andhydrobromide which are preferred, sulfate, nitrate, phosphate, borate,acetate, tartrate, maleate, citrate, succinate, oxalate, benzoate,ascorbate, salicylate, methanesulfonate, benzenesulfonate,toluenesulfonate and the like.

The compounds of formula I, and the pharmaceutically acceptable acidaddition salts thereof, are useful in treating inflammation in mammalianspecies, e.g., rats, dogs, cats, monkeys, etc. Joint tenderness andstiffness (in conditions such as rheumatoid arthritis) are relieved bythe above described compounds.

The compounds of this invention can be formulated for use asantiinflammatory agents according to accepted pharmaceutical practice inoral dosage forms such as tablets, capsules, elixirs, or powders, or inan injectable form in a sterile aqueous vehicle prepared according toconventional pharmaceutical practice. The compounds of this inventionmay be administered in amounts of 100 mg/70kg/day to 2 g/70kg/day,preferably 100 mg/70kg/day to 1 g/70kg/day.

The following examples are specific embodiments of this invention.

EXAMPLE 12,3,3a,4,6,7-Hexahydro-3-phenyl-7-(phenylmethylene)-2-propylpyrano[4,3-c]pyrazole

A mixture of 3.6g of tetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-oneand 1.1g of n-propylhydrazine in 250 ml of methanol is heated at refluxtemperature for 3 to 4 hours. Methanol is removed in vacuo, and theresidue is dissolved in chloroform. The chloroform solution is washedwith dilute hydrochloric acid and water. The organic layer is then driedover anhydrous magnesium sulfate and concentrated in vacuo to give 4g ofa crude oil. This is triturated with about 10 ml of acetonitrile andleft at room temperature overnight. Some crystals precipitate out andare collected by filtration. The filtrate is concentrated and applied toa dry packed alumina column (neutral, activity I). The fractions elutedwith hexane are combined with the crystals obtained above andrecrystallized from ether/hexane to yield the title compound, meltingpoint 113.5°-115° C.

EXAMPLES 2-22

Following the procedure of Example 1, but substituting the compoundlisted in column I fortetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-one and the compoundlisted in column II for n-propylhydrazine, yields the compound listed incolumn III.

    __________________________________________________________________________    Example    Column I        Column II         Column III                       __________________________________________________________________________    2     tetrahydro-3,5-bis-[(4-methyl-                                                                   benzylhydrazine                                                                            3-(4-methylphenyl)-7-[(4-methylpheny                                          l)-                                           phenyl)methylene]-4H-pyran-4-one                                                                              methylene]-2-benzyl-2,3,3a,4,6,7-hex                                          a-                                                                            hydropyrano[4,3-c]pyrazole              3     tetrahydro-3,5-bis-[(4-cyano-                                                                    ethylhydrazine                                                                             3-(4-cyanophenyl)-7-[(4-cyanophenyl)                                          -                                             phenyl)methylene]-4H-pyran-4-one                                                                              methylene]-2-ethyl-2,3,3a,4,6,7-hexa                                          -                                                                             hydropyrano[4,3-c]pyrazole              4     tetrahydro-3,5-bis-[(4-nitro-                                                                    n-octylhydrazine                                                                           2,3,3a,4,6,7-hexahydro-3-(4-nitrophe                                          nyl)-                                         phenyl)methylene]-4H-pyran-4-one                                                                              7-[(4-nitrophenyl)methylene]-2-octyl                                          -                                                                             pyrano[4,3-c]pyrazole                   5     tetrahydro-3,5-bis-[[4-(dimethyl-                                                                phenylhydrazine                                                                            3-[4-(dimethylamino)phenyl]-7-[                                               [4-(dimethyl-                                 amino)phenyl]methylene]-4H-pyran-                                                                             amino)phenyl]methylene]-2,3,3a,4,6,7                                          -hexa-                                        4-one                           hydro-2-phenylpyrano[4,3-c]pyrazole     6     tetrahydro-3,5-bis-[(3-hydroxy-                                                                  ethylhydrazine                                                                             2-ethyl-2,3,3a,4,6,7-hexahydro-3-(3-                                          hydroxy-                                      phenyl)methylene]-4H-pyran-4-   phenyl)-7-[(3-hydroxyphenyl)methylen                                          e]-                                           one                             pyrano[4,3-c]pyrazole                   7     tetrahydro-3,5-bis-[(4-methylthio-                                                               benzylhydrazine                                                                            2-benzyl-2,3,3a,4,6,7-hexahydro-3-(4                                          -methyl-                                      phenyl)methylene]-4H-pyran-4-one                                                                              thiophenyl)-7-[(4-methylthiophenyl)m                                          ethylene]-                                                                    pyrano[4,3-c]pyrazole                   8     tetrahydro-3,5-bis-[(4-ethylsul-                                                                 phenylhydrazine                                                                            3-(4-ethylsulfinylphenyl)-7-[(4-ethy                                          lsulfinyl-                                    finylphenyl)methylene]-4H-pyran-                                                                              phenyl)methylene]-2,3,3a,4,6,7-hexah                                          ydro-2-                                       4-one                           phenylpyrano[4,3-c]pyrazole             9     tetrahydro-3,5-bis-[(2-methyl-                                                                   methylaminopropyl-                                                                         3a,4,6,7-tetrahydro-N-methyl-3-(2-            phenyl)methylene]-4H-pyran-4-one                                                                 hydrazine    methylphenyl)-7-[(2-methylphenyl)-                                            methylene]pyrano[4,3-c]pyrazole-2(3H                                          )-                                                                            propanamine                             10    tetrahydro-3,5-bis-[ (4-methoxy-                                                                 N-benzyl-N-methyl-                                                                         3a,4,6,7-tetrahydro-N-benzyl-N-               phenyl)methylene]-4H-pyran-4-one                                                                 aminoethylhydrazine                                                                        methyl-3-(4-methoxyphenyl)-7-                                                 [(4-methoxyphenyl)methylene]pyrano-                                           [4,3-c]pyrazole-2(3H)-ethanamine        11    tetrahydro-3,5-bis-[(4-trifluoro-                                                                N-methyl-N-phenyl-                                                                         3a,4,6,7-tetrahydro-N-methyl-N-               methylphenyl)methylene]-4H-pyran-                                                                aminopentylhydrazine                                                                       phenyl-3-(4-trifluoromethylphenyl)-           4-one                           7-[(4-trifluoromethylphenyl)methyl-                                           ene]pyrano[4,3-c]pyrazole-2(3H)-                                              pentanamine                             12    tetrahydro-3,5-bis-[(2-chloro-                                                                   (2-aminoethyl)hydra-                                                                       3a,4,6,7-tetrahydro-3-(2-chloro-              phenyl)methylene]-4H-pyran-4-one                                                                 zine         phenyl)-7-[2-(chlorophenyl)methylene                                          ]-                                                                            pyrano[4,3-c]pyrazole-2(3H)-ethanami                                          ne                                      13    tetrahydro-3,5-bis-(phenylmethyl-                                                                phenylaminopropyl-                                                                         3a,4,6,7-tetrahydro-N-phenyl-3-pheny                                          l-                                            ene)-4H-pyran-4-one                                                                              hydrazine    7-(phenylmethylene)pyrano[4,3-c]pyra                                          zole-                                                                         2(3H)-propanamine                       14    tetrahydro-3,5-bis-(phenylmethyl-                                                                benzylaminopropyl-                                                                         3a,4,6,7-tetrahydro-N-benzyl-3-pheny                                          l-                                            ene)-4H-pyran-4-one                                                                              hydrazine    7-(phenylmethylene)pyrano[4,3-c]pyra                                          zole-                                                                         2(3H)-propanamine                       15    tetrahydro-3,5-bis-[(4-propoxy-                                                                  3-(dimethylamino)-                                                                         3a,4,6,7-tetrahydro-N,N,β-trime                                          thyl-3-                                       phenyl)methylene]-4H-pyran-                                                                      2-methyl-propyl-                                                                           (4-propoxyphenyl)-7-[(4-propoxypheny                                          l)-                                           4-one              hydrazine    methylene]pyrano[4,3-c]pyrazole-2(3H                                          )-                                                                            propanamine                             16    tetrahydro-3,5-bis-(phenyl-                                                                      3-(4-methyl-1-piper-                                                                       2,3,3a,4,6,7-hexahydro-2-[3-(4-               methylene)-4H-pyran-4-one                                                                        azinyl)propylhydrazine                                                                     methyl-1-piperazinyl)propyl]-3-                                               phenyl-7-(phenylmethylene)pyrano-                                             [4,3-c]pyrazole; melting point                                                101-104° C; melting point of                                           di-                                                                           maleate salt 173-175° C          17    tetrahydro-3,5-bis-[(4-methyl-                                                                   3-(4-methyl-1-piper-                                                                       2,3,3a,4,6,7-hexahydro-2-[3-(4-               sulfinyl)phenylmethylene]-4H-                                                                    azinyl)propylhydrazine                                                                     methyl-1-piperazinyl)propyl]-3-               pyran-4-one                     [4-(methylsulfinyl)phenyl]-7-[4-              pyran-4-one                     [4-(methylsulfinyl)phenyl]-7-[4-                                              (methylsulfinyl)phenylmethylene]-                                             pyrano[4,3-c]pyrazole; melting                                                point of dimaleate salt                                                       172-174° C                       18    tetrahydro-3,5-bis-(phenyl-                                                                      2-(1-piperazinyl)ethyl-                                                                    2,3,3a,4,6,7-hexahydro-2-[2-(1-               methylene)-4H-pyran-4-one                                                                        hydrazine    piperazinyl)ethyl]-3-phenyl-7-                                                (phenylmethylene)pyrano[4,3-c]-                                               pyrazole                                19    tetrahydro-3,5-bis-(phenyl-                                                                      3-(4-phenyl-1-pipera-                                                                      2,3,3a,4,6,7-hexahydro-2-[3-(4-               methylene)-4H-pyran-4-one                                                                        zinyl)propylhydrazine                                                                      phenyl-1-piperazinyl)propyl]-3-                                               phenyl-7-(phenylmethylene)pyrano-                                             [4,3-c]pyrazole                         20    tetrahydro-3,5-bis-(phenyl-                                                                      4-(4-phenylmethyl-1-                                                                       2,3,3a,4,6,7-hexahydro-2-[4-(4-               methylene-4H-pyran-4-one                                                                         piperazinyl)butylhydra-                                                                    phenylmethyl-1-piperazinyl)butyl]-                               zine         3-phenyl-7-(phenylmethylene)pyrano-                                           [4,3-c]pyrazole                         21    tetrahydro-3,5-bis-(2-methyl-                                                                    3-(4-morpholinyl)propyl-                                                                   2,3,3a,4,6,7-hexahydro-2-[3-(4-               phenyl)methylene]-4H-pyran-4-one                                                                 hydrazine    morpholinyl)propyl]-3-(2-methyl-                                              phenyl)-7-[(2-methylphenyl)methylene                                          ]-                                                                            pyrano[4,3-c]pyrazole                   22    tetrahydro-3,5-bis-(phenyl-                                                                      2-(1-piperidinyl)ethyl-                                                                    2,3,3a,4,6,7-hexahydro-2-[2-(1-piper                                          -                                             methylene)-4H-pyran-4-one                                                                        hydrazine    idinyl)ethyl]-3-phenyl-7-(phenyl-                                             methylene)pyrano[4,3-c]pyrazole         __________________________________________________________________________

What is claimed is:
 1. A compound having the formula ##STR8##or apharmaceutically acceptable salt thereof, wherein R₁ is hydrogen,hydroxy, alkyl, alkoxy, alkylthio, trifluoromethyl, halogen, nitro,cyano, dialkylamino or alkylsulfinyl; and R₂ is hydrogen, alkyl, aryl,arylalkyl, X-C- wherein X is alkyl or aryl, or A-NR₃ R₄ wherein A is astraight or branched chain alkylene group having 2 to 5 carbon atoms, R₃is hydrogen or alkyl, and R₄ is hydrogen, alkyl, phenyl or phenylalkyl,or R₃ and R₄ together with the nitrogen atom to which they are attachedare ##STR9##wherein Z is CH₂, oxygen or N-R₅ wherein R₅ is hydrogen,alkyl, aryl or arylalkyl; wherein the terms alkyl and alkoxy refer togroups having 1 to 8 carbon atoms and the term aryl refers to phenyl orphenyl monosubstituted with an alkyl, alkoxy, halogen or trifluoromethylgroup.
 2. A compound in accordance with claim 1 wherein R₂ is hydrogen,alkyl, aryl, arylalkyl, or X-C- wherein X is alkyl or aryl.
 3. Acompound in accordance with claim 1 wherein R₂ is A-NR₃ R₄.
 4. Acompound in accordance with claim 3 wherein R₃ is hydrogen or alkyl andR₄ is hydrogen, alkyl, phenyl or phenylalkyl.
 5. A compound inaccordance with claim 3 wherein NR₃ R₄ is ##STR10##
 6. A compound inaccordance with claim 5 wherein Z is N-R₅.